MedComm - Future medicine最新文献

Protein structure prediction (PSP) has been a prominent topic in bioinformatics and computational biology, aiming to predict protein function and structure from sequence data. The three-dimensional conformation of proteins is pivotal for their intricate biological roles. With the advancement of computational capabilities and the adoption of deep learning (DL) technologies (especially Transformer network architectures), the PSP field has ushered in a brand-new era of “neuralization.” Here, we focus on reviewing the evolution of PSP from traditional to modern deep learning-based approaches and the characteristics of various structural prediction methods. This emphasizes the advantages of deep learning-based hybrid prediction methods over traditional approaches. This study also provides a summary analysis of widely used bioinformatics databases and the latest structure prediction models. It discusses deep learning networks and algorithmic optimization for model training, validation, and evaluation. In addition, a summary discussion of the major advances in deep learning-based protein structure prediction is presented. The update of AlphaFold 3 further extends the boundaries of prediction models, especially in protein-small molecule structure prediction. This marks a key shift toward a holistic approach in biomolecular structure elucidation, aiming at solving almost all sequence-to-structure puzzles in various biological phenomena.

Corneal epithelial ingrowth (EI) is a rare but significant complication following Small Incision Lenticule Extraction (SMILE) surgery. During the procedure, the opaque bubble layer (OBL) formation may create microchannels that disrupt Bowman's layer, providing a pathway for epithelial cells to migrate into the corneal stroma. In this study, we investigated the mechanisms behind EI development and proposed preventive strategies. We analyzed four cases of EI post-SMILE surgery, utilizing anterior segment optical coherence tomography (AS-OCT) and corneal tomography for diagnosis. Preventive measures, including careful anesthetic application and precise suction cone positioning, were employed to minimize OBL formation. Here, we show that subflap debris removal surgery led to significant clinical improvement, with no EI recurrence observed. Our findings suggest that the microchannels created by OBL during surgery may play a crucial role in EI development, challenging previous assumptions that EI is primarily due to trauma at the flap edges. This underscores the importance of precise surgical technique and effective postoperative management. Further research, including clinical studies and advanced imaging, is needed to confirm this proposed mechanism and improve outcomes in refractive surgery. The study highlights the necessity for ongoing advancements in surgical protocols and technology to prevent and manage EI effectively.

Coronavirus disease 2019 (COVID-19) pandemic has caused millions of deaths. The risk of COVID-19 spreading still exists after the deconfinement act, Omicron became the dominant variant. Although N6-methyladenosine (m⁶A) regulators has been reported to affect the pathogenicity of COVID-19, their mechanism in the progression of lung injury in COVID-19 patients remain elusive. Here we show the landscape and specific mechanisms of m⁶A regulators in lung tissues through single-nucleus RNA sequencing (snRNA-Seq) data sets of 116,252 cells, and the external validation was performed using data from another snRNA-Seq data. The m⁶A reader IGF2BP2 was specifically upregulated in alveolar type I (AT1) cells, resulting in impaired lung regeneration. ALKBH5 expression upregulation in macrophages, impairing immune responses. Moreover, WTAP markedly upregulated in fibroblasts, leading to pulmonary fibrosis. In addition, m⁶A regulators dysregulation induced aberrant cell–cell communication in pulmonary tissue and mediated ligand–receptor interactions across diverse cell types in lung tissues by activating the TGF-β signaling pathway. Overall, these results indicated that the upregulation of m⁶A regulators in alveolar cells, myeloid cells, and fibroblasts may induce pulmonary injury in patients. The development of m⁶A-regulator inhibitors could be as one potential antifibrotic drugs for COVID-19.

In a recent paper published in Cell, Battaglia et al. provide a valuable pan-cancer analysis of the microbiome in metastatic cancer,¹ which identified the specific preferences of microbes for different organs and demonstrated the correlations between diversity of microbes and neutrophils invasive into tumors, the anaerobic bacterial enrichments in hypoxic tumors, and the relationship between Fusobacterium and immune checkpoint blockade resistance in nonsmall cell lung cancer.

For over a century, researchers have observed the presence of bacteria in human tumors. However, the pathophysiological impact of intratumor microbiomes has been consistently ignored. Because of this overlook, despite our extensive knowledge of cancer and our array of treatment options, the microbiome has just been linked to cancer studies in the recent 20 years. Even though only a small number of bacteria are known to be directly carcinogenic, there has been a consistent rise in the number of bacteria that have an indirect impact on cancer.

The microbiome has been found to be linked to the tumor microenvironment, the initiation of innate immune sensing pathways, the tumor-infiltrating immune compartment, and the effectiveness of immunotherapy. The presence of microbes in local tissue, adjacent locations, and tumors themselves has been demonstrated to foster and inhibit the onset and growth of cancer. Moreover, these microbes have demonstrated the ability to influence the effectiveness of many cancer treatments, such as radiation, chemotherapy, and immunotherapy, which play a vital part in regulating the host immune system and influencing the body's response to anticancer treatments (Figure 1). Primary tumors contain intricate microbial communities, and current research indicates that certain types of cancer are significantly influenced by these microbes. In our view, it is crucial to comprehend the impact of the bacteria that exist in tumors on tumor biology, immunology, and therapeutic response. However, little is known about the existence and significance of the microbiome in relation to cancer, including the distinction in the microbial composition between the primary tumor and its metastases, the preferential colonization of bacteria in certain tumor types or organs, and the resilience of the microbial population during therapeutic interventions.

To this end, Battaglia et al. combined metagenomics, genomics, and transcriptomics techniques to examine the microbiota of metastatic tumors and their tumor-resident microbiome. They employed a bioinformatics methodology for data analysis, utilizing computational approaches such as Kraken2 and PathSeq, and also used high-throughput sequencing technology and various bioinformatics analysis approaches, including the STAR RNA-seq comparison tool and MutationalPatterns analysis, to enhance the precision and comprehensiveness of data processing and analysis. They analyzed 4164 samples of

In recent publications,^{1, 2} the group of Professor Zhu Shu/Pan Wen and the research team of Wang Liangjing/Chen Shujie, respectively investigated two intestinal microbial metabolites: deoxycholic acid (DCA) and indole-3-propionic acid (IPA). DCA acts on the calcium ion channel plasma membrane Ca²⁺ ATPase (PMCA), inhibits the effector function of CD8⁺ T cells and consequently promotes colorectal cancer (CRC) growth. IPA activates precursor-exhausted T (T_pex) cells and induces their transformation into effector T (T_eff) cells, thereby increasing T-cell infiltration into the tumor tissue and enhancing the efficacy of immunotherapy (Figure 1).

Zhu et al. screened 73 small-molecule compounds derived from microbial sources to examine their effects on CD8⁺ T-cell-mediated cytotoxicity or IFN-γ production, and identified DCA. Subsequent experiments using sodium dodecyl sulfate (SDS) or other chemical inhibitors confirmed that DCA does not lead to cell death. In tumor immunity, CD8⁺ T cells are crucial in resisting tumors, with cytokines such as IFN-γ and TNF-α playing key roles in killing tumor cells. CD8⁺ T-cell activation relies on Ca²⁺ as a second messenger and the cytoplasmic Ca²⁺ concentration directly affects CD8⁺ T-cell activation. The authors found that DCA could inhibit cytoplasmic Ca²⁺ accumulation by monitoring the real-time fluorescence intensity of cytoplasmic Ca²⁺ in anti-CD3/CD28-activated CD8⁺ T cells.

NFAT2 is an important transcription factor regulating CD8⁺ T cells.³ According to immunoblotting results, DCA reduced the transcription of this factor. Using NFAT2-luciferase reporter gene assays, the authors observed that PMA/ionomycin stimulation increased the transcriptional activity of NFAT2. Notably, DCA supplementation attenuated this transcriptional activation, indicating that DCA could inhibit the NFAT2-mediated transcription induced by Ca²⁺ influx. To further study the specific effects of DCA, the authors examined several key observations. First, DCA did not reduce the levels of free calcium ions in cell-free culture medium, indicating that DCA does not chelate calcium ions. Second, the calcium-release activated channel (CRAC) was the main inward pathway. The immunosuppressive impact of DCA on CD8⁺ T cells persisted despite the presence of the selective CRAC channel blocker, BTP2, indicating that DCA did not affect calcium influx. Third, PMA/ionomycin induces Ca²⁺ to be released directly from the endoplasmic reticulum without relying on transporter proteins.^{1, 4} However, DCA inhibits Ca²⁺ accumulation, indicating that Ca²⁺ may flow out of the cell membrane in large quantities or into intracellular stores. Therefore, having blocked various ch

Idiopathic pulmonary fibrosis (IPF) represents a chronic interstitial lung disease with an unclear underlying mechanism and currently lacks a definitive treatment. Cordyceps sinensis (CS), renowned for its pharmacological properties in traditional Chinese medicine and extensive use in lung disease treatment, holds promise as a therapeutic agent for IPF. However, the specific role of CS in treating IPF remains unclear. In this study, we aimed to assess the efficacy of CS in treating IPF and unravel potential underlying mechanisms. Our results demonstrate that CS treatment effectively mitigated pulmonary inflammation and collagen deposition in bleomycin-induced IPF mice. Proteomics analysis revealed that the regulation of mitochondrial oxidative phosphorylation may serve as a potential protective mechanism of CS against IPF in mice. Further investigation unveiled that CS could suppress the excessive production of mitochondrial reactive oxygen species in lung tissues induced by bleomycin through moderating the expression and activity of mitochondrial complexes, thus safeguarding the integrity and function of mitochondria. Overall, our findings not only underscore the effectiveness of CS in preventing bleomycin-induced IPF but also highlight mitochondrial-mediated oxidative stress as a promising therapeutic target for treating IPF.

Metabolic reprogramming in cancer significantly impacts immune responses within the tumor microenvironment, but its influence on cancer immunotherapy effectiveness remains uncertain. This study aims to elucidate the prognostic significance of metabolic genes in cancer immunotherapy through a comprehensive analytical approach. Utilizing data from the IMvigor210 trial (n = 348) and validated by retrospective datasets, we performed patient clustering using non-negative matrix factorization based on metabolism-related genes. A metabiotic score was developed using a “DeepSurv” neural network to assess correlations with overall survival (OS), progression-free survival, and immunotherapy response. Validation of the metabolic score and key genes was achieved via comparative gene expression analysis using qPCR. Our analysis identified four distinct metabolic classes with significant variations in OS. Notably, the metabolism-inactive and hypoxia-low class demonstrated the most pronounced benefit in terms of OS. The metabolic score predicted immunotherapeutic benefits with high accuracy (AUC: 0.93 at 12 months). SETD3 emerged as a crucial gene, showing strong correlations with improved OS outcomes. This study underscores the importance of metabolic profiling in predicting cancer immunotherapy success. Specifically, patients classified as metabolism-inactive and hypoxia-low appear to derive substantial benefits. SETD3 is established as a promising prognostic marker, linking metabolic activity with patient outcomes, advocating for the integration of metabolic profiling into immunotherapy strategies to enhance treatment precision and efficacy.

The end of second decade in the 21st century witnessed a prominent disease outbreak caused by the novel coronavirus SARS-CoV-2 (including most diverse omicron subvariants), where the death toll crossed the boundary of 6.9 million across the globe by December 19, 2023. All spheres of central dogma of molecular biology and host‒pathogen interaction was explored to find ways in diagnostics, isolation, curtailment, and therapy. Above all, diagnostics and therapeutics against COVID-19 took an enormous jump, which needs to be evaluated for accuracy and feasibility and requires serious compilation for current and future generations. With the same objective, this review encompasses the diverse ways including prevention practiced and proposed during the handling of this pandemic across the globe. It involves the role of mutations in viruses and subsequent epitope mapping with potential immune escape mechanisms of SARS-CoV-2 variants including the conservancy of T-cell epitopes has also been highlighted. The efficacy in antigen/antibody-based diagnostics, RT‒PCR- and NGS-based confirmation of pathogen presence, and imaging (X-ray/CT-scan) for symptoms and damage assessment has been thoroughly filtered. The possibility of errors in diagnostics and their cause and consequences have also been presented for the ease of readers and further improvisers.